Traumatic brain injury (TBI) is one of the leading causes of disability in our society. Unfortunately, there is no specific treatment for TBI. Brain derived neurotrohic factor (BDNF) is a key player in neuronal survival, growth and plasticity. These qualities provide it with therapeutic capabilities. However, BDNF-based treatments have been limited by delivery problems. I propose to endogenously upregulate BDNF and associated molecular systems with exercise following TBI. The concept of endogenously upregulating molecules important in synaptic plasticity after TBI is an uncharted area of research that could have an impact on rehabilitative startegies. However, during the first days to weeks following TBI, the brain is in a state of energy crisis that may compromise the reactivity of molecular systems to physiological stimulation as a result of exercise. I would like to determine to what degree BDNF and associated molecular systems respond to TBI and subsequent voluntary exercise. In order to address this topic the following specific aims are proposed to: Specific Aim 1: Determine if injury-induced changes in BDNF and associated proteins involved with synaptic plasticity are time and severity dependent. Within this aim I will determine the effects of a lateral fluid percussion injury (FPI) on hipppocampal and cortical BDNF (and associated molecules) at postinjury times that are pertinent to the recovery and rehabilitative period. Specific Aim 2: Determine the post-traumatic time window in which exercise can produce an endogenous up-regulation of BDNF (and its associated molecular systems). Within this aim I will determine the period of time following injury when voluntary exercise does not result in an up-regulation of BDNF and determine if this time window is injury-severity dependent. Specific Aim 3: Determine the short and long-term effects of exercise on cognitive outcome and determine if any exercise-induced improvement is dependent on BDNF. The Morris Water Maze (MWM) will be used to assess learning acquisition and memory performance. In order to address these specific aims, I will utilize the lateral fluid-percussion injury model in rats and voluntary running wheel exposure. Protein, gene, histological and behavioral studies will be conducted.